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| United States Patent |
5,521,280
|
|
Reilly
, et al.
|
May 28, 1996
|
Reinforced absorbable polymers
Abstract
A composition of an absorbable polymer and a filler to increase the
stiffness of the polymer is disclosed. The filler is a poly[succinimide],
which is a bioabsorbable polymer that degrades into a nontoxic, simple
amino acid. The composition can be melt processed to prepare medical and
surgical devices, particularly those devices which are designed to
penetrate bodily tissue or to withstand heavy loads. Typical surgical
devices which can be made from the composition include surgical staples
and ligating clips.
| Inventors:
|
Reilly; Eugene P. (Lawrenceville, NJ);
Arnold; Steven C. (Franklin, NJ);
Scopelianos; Angelo G. (Whitehouse Station, NJ)
|
| Assignee:
|
Ethicon, Inc. (Somerville, NJ)
|
| Appl. No.:
|
388548 |
| Filed:
|
February 14, 1995 |
| Current U.S. Class: |
528/370; 424/422; 525/417; 606/151; 606/154; 606/230 |
| Intern'l Class: |
C08G 064/00; A61B 017/08; C08F 283/04 |
| Field of Search: |
606/151,154
528/370
525/417
|
References Cited
U.S. Patent Documents
| 4052988 | Oct., 1977 | Namassivaya et al. | 128/335.
|
| 4279249 | Jul., 1981 | Vert et al. | 525/415.
|
| 4473670 | Sep., 1984 | Kessidis | 523/105.
|
| 4612923 | Sep., 1986 | Kronenthal | 128/92.
|
| 4646741 | Mar., 1987 | Smith | 128/334.
|
| 4741337 | May., 1988 | Smith et al. | 128/334.
|
| 4743257 | May., 1988 | Tomala et al. | 525/411.
|
| 4888398 | Dec., 1989 | Bichen et al. | 525/420.
|
| 5137928 | Sep., 1992 | Erbel et al. | 528/170.
|
| 5152781 | Oct., 1992 | Tang et al. | 528/354.
|
| 5175285 | Dec., 1992 | Lehman et al. | 544/141.
|
| 5286810 | Feb., 1994 | Wood | 525/421.
|
| 5412068 | May., 1995 | Tang et al. | 606/230.
|
Other References
S. W. Fox, J. E. Johnson, & M. Middleebrook, J. Am. Chem. Soc., 77, 1048
(1955).
A. Vegotsky, K. Harada, & S. W. Fox, J. Am. Chem. Soc., 80, 3361 (1958).
K. Harada, J. Org. Chem., 24, 1662 (1959).
P. Neri & G. Antoni, Macromol. Synth., 8, 25 (1982).
|
Primary Examiner: Yoon; Tae
Attorney, Agent or Firm: Woodrow; Hal Brent
Parent Case Text
BACKGROUND OF THE INVENTION
This is a division of application Ser. No. 08/208,391, filed Mar. 8, 1994,
now U.S. Pat. No. 5,397,816, which is hereby incorporated by reference
which is a continuation-in-part of Ser. No. 07/977,333 filed Nov. 17,
1992, now abandoned which is incorporated herein by reference.
Claims
We claim:
1. A surgical device comprising an absorbable matrix comprising an
absorbable polymer selected from the group consisting of aliphatic
polyanhydrides, aromatic polyanhydrides polylactones homopolymers,
polylactone copolymers, poly(esteranhydrides), polyiminocarbonates,
polyesters of oxalic acid, polyesters of malic acid, polyesters of
tartaric acid, polyamides, poly(aminoacids), nontoxic polypeptides,
poly(hydroxybutyrate), poly(hydroxybutyrate-co-hydroxyvalerate),
bacterially derived polyesters, polyphosphazenes, polyesteramides and
block copolymers of polyethylene glycol and polylactones capable of being
absorbed by the body containing as a discrete filler material, a
poly[succinimide], in an amount sufficient to increase the stiffness of
the polymer, having repeating units represented by the following formula:
##STR2##
2. The device of claim 1 wherein the device is a surgical staple.
3. The device of claim 1 wherein the device is a ligating clip.
4. The device of claim 1 wherein the synthetic absorbable polymer is
derived from at least one lactone monomer.
5. The device of claim 4 wherein the lactone monomer is selected from the
group consisting of lactide, glycolide, 1,4-dioxanone, trimethylene
carbonate, .delta.-valerolactone, .epsilon.-caprolactone,
1,4-dioxepan-2-one, 1,5-dioxepan-2-one, cyclic dimers thereof and
combinations of two or more thereof.
6. The device of claim 4 wherein the absorbable polymer is selected from
the group consisting of homopolymers of 1,4-dioxanone and copolymers of
lactide and glycolide.
7. The device of claim 6 wherein the absorbable polymer is a homopolymer of
1,4-dioxanone.
8. The device of claim 1 wherein the amount of the poly[succinimide] filler
in the absorbable polymer is between about 10 to about 80 percent of the
weight of the composition.
9. The device of claim 1 wherein the amount of the poly[succinimide] filler
in the absorbable polymer is between about 20 to about 40 percent of the
weight of the composition.
Description
This invention relates to compositions of absorbable polymers containing a
bioabsorbable filler. More specifically, it relates to absorbable polymer
compositions containing a reinforcing filler which enhances the stiffness
of the polymer composition, yet decomposes into components which are
biocompatible with bodily tissue.
The need to replace surgical and medical devices made of metallic
components continues to grow as surgical procedures become more intricate
and complex. The driving force for the replacement of such metallic
devices is the need for devices composed of materials which are capable of
being absorbed by the body. Bioabsorbable materials obviously represent a
significant advantage over metallic materials, in that bioabsorbable
materials do not need to be removed after their surgical function has been
accomplished. In contrast, metallic devices remain in the body and often
require removal when the surgical repair is completed to prevent possible
adverse reactions occurring due to the prolonged contact of the metallic
device and the surrounding bodily tissue or due to the byproducts of the
corrosion of the metal.
As a result of the burgeoning need for bioabsorbable materials in surgery
and for other medical applications, a body of art has been developed which
utilizes bioabsorbable polymers as the structural component of these
devices. In this manner, once the device has performed its function, the
bioabsorbable polymer from which it is composed readily breaks down into
nontoxic segments which can be metabolized or passed through bodily
tissue. For example, U.S. Pat. No. 4,052,988 describes preparing
absorbable surgical devices from polymers of 1,4-dioxanone and
1,4-dioxepan-2-one. The devices which can be prepared from these
absorbable polymers include sutures, tubular implants, surgical meshes,
staples, and cylindrical pins, rods or screws. The properties of the
polymers from which the devices are made can be changed by copolymerizing
1,4-dioxanone or 1,4-dioxepan-2-one with other lactone monomers, such as
lactide or glycolide, or by forming mixtures of the homopolymers with
other absorbable polymers.
Other examples exist of the use of bioabsorbable polymers as the main
component for surgical devices. U.S. Pat. No. 4,741,337 describes surgical
fasteners, particularly staples, composed of a polymeric blend derived
from homopolymers and copolymers of lactide and glycolide. The blending of
the polymers is optimized to yield fasteners which can retain their
strength in vivo for prolonged time periods, yet become impalpable shortly
thereafter.
Another example of surgical devices made from absorbable polymers can be
found in U.S. Pat. No. 4,646,741. This patent describes surgical fasteners
made from polymeric blends. The blends contain a copolymer of lactide and
glycolide and a homopolymer of 1,4-dioxanone. Once again, the proportion
of polymers in the blend is carefully controlled to achieve the optimum
properties for the fastener.
While absorbable, polymeric surgical and medical devices represent an
advantage over metallic devices because the polymeric devices do not need
to be removed from the body, such polymeric devices often have a major
drawback which has limited their applications. Specifically, absorbable
polymers typically lack the strength and stiffness of metallic components.
Strength is an important asset for devices designed to penetrate bodily
tissue or to withstand heavy loads. For these applications, the absorbable
polymers must be stiff enough to withstand the penetration forces or the
load placed on them. With respect to this important attribute of
stiffness, absorbable polymers are usually incapable of matching the
performance characteristics of metals and metal alloys used for surgical
devices.
Accordingly, attempts have been made to increase the stiffness of
bioabsorbable polymers from which surgical and medical devices are made.
U.S. Pat. No. 4,473,670 describes preparing absorbable polymers containing
finely divided sodium chloride or potassium chloride for surgical devices
such as ligating clips and staples. The salt filler enhances certain
properties of the polymer, most notably its stiffness. The absorbable
polymers which can be used include homopolymers and copolymers of lactide,
glycolide, and 1,4-dioxanone. In a similar manner, U.S. Pat. No. 4,612,923
discloses another example of using a filler to increase the stiffness of
an absorbable polymer. In this case, an absorbable glass is used as the
filler.
Unfortunately, the use of bioabsorbable glasses or inorganic salts as
fillers for bioabsorbable polymers has certain disadvantages. First, since
the absorbable polymer matrix is organic material, and the fillers
described in these patents are inorganic compounds, the adhesion between
the absorbable polymer matrix and the filler may be less than desirable
for adequate performance. That is, a lack of adhesion between the filler
and the polymer matrix will tend to reduce the synergistic effects of
their combination, and significant improvements in stiffness may not be
realized. Second, the use of an absorbable glass filler may cause the
calcification of soft tissue when the device from which the glass filled
polymer degrades inside the body.
In view of the deficiencies of the prior art, what is needed is a
bioabsorbable filler for absorbable polymers in which the filler can
readily break down into biocompatible segments. In addition, and most
importantly, what is also needed is an organic compound that is used as a
reinforcing filler and is compatible with the absorbable polymer matrix so
that good adhesion and blending can be established for the optimum
improvement in the properties, especially the stiffness of the polymer.
SUMMARY OF THE INVENTION
The invention is a composition comprising an absorbable polymer capable of
being absorbed by the body. The polymer contains as a filler a
poly[succinimide] in an amount sufficient to increase the stiffness of the
polymer.
Surprisingly, the poly[succinimide] filler increases the stiffness of an
injection molded device made of an absorbable polymer as measured by the
Young's modulus of that device in comparison to an injection molded part
which does not contain the poly[succinimide] filler. Poly[succinimide]
biodegrades into a nontoxic, simple amino acid, which can readily be
eliminated in the body.
Contrary to the use of absorbable glasses as fillers for absorbable
polymers, there is no calcification of tissues when poly[succinimide] is
used as the filler for the polymer. Additionally, poly[succinimide] is an
organic polymer which, unlike the inorganic fillers described in the art,
is compatible with the absorbable polymer matrix. In this manner, the
adhesion between the absorbable polymer and poly[succinimide] filler is
greater than that which would be achieved between the absorbable polymer
and the inorganic glass or salt fillers. Moreover, this inherently good
adhesion between the polymer matrix and the poly[succinimide] filler may
be improved by surface treatments prior to the blending operation.
Therefore, significant increases in the stiffness of the absorbable
polymer composition can be achieved by incorporating the organic,
poly[succinimide] filler into the absorbable polymer composition.
Finally, poly[succinimide] is an amorphous polymer which has a very high
glass transition temperature of about 200.degree. C. The significance of
this property is that the polysuccinimide does not soften or react when it
is incorporated into the absorbable polymer composition at processing
temperatures below its glass transition temperature. Thus, the
poly[succinimide] filler is easy to process and successfully incorporate
into the absorbable polymer composition to improve the stiffness of the
polymer.
The compositions of this invention can be used for any application in which
such compositions can be envisioned, but they are especially useful for
the preparation of medical and surgical devices.
DETAILED DESCRIPTION OF THE INVENTION
Poly[succinimides] are known polymeric compounds, and the synthesis of
poly[succinimide] by the thermal polymerization of aspartic acid is
reported in the following references: S. W. Fox, J. E. Johnson, and M.
Middlebrook, J. Am. Chem. Soc., 77, 1048 (1955); J. Kovacs, I. Koenyves,
and A. Pusztai, Experientia, 9, 459 (1959); J. Kovacs and I. Koenyves,
Naturwiss, 41, 333 (1953); A. Vegotsky, K. Harada, and S. W. Fox, J. Am.
Chem. Soc., 80, 3361 (1958); K. Harada, J. Org. Chem., 24, 1662 (1959). An
improved synthesis of poly[succinimide] was published and involved the
polycondensation of D,L-aspartic acid using 85 weight percent phosphoric
acid. See P. Neri and G. Antoni, Macromol. Synth., 8, 25 (1982).
For the purpose of defining this invention, a poly[succinimide] is any
polymer derived from aspartic acid, aspartic acid anhydride, or any
substituted equivalent of aspartic acid or aspartic acid anhydride,
including all possible combinations of stereoisomers of these compounds.
In addition, a poly[succinimide] is any polymerization reaction product
which would yield the structural equivalent of any of the polymers
described in the preceding sentence. The most preferred poly[succinimide]
is a polymer which has repeating units represented by the following
chemical formula:
##STR1##
A polymer is "absorbable" within the meaning of this invention if it is
capable of breaking down into small, nontoxic segments which can be
metabolized or eliminated from the body without harm. Generally,
absorbable polymers swell, hydrolyze, and degrade upon exposure to bodily
tissue, resulting in a significant weight loss. The hydrolysis reaction
may be enzymatically catalyzed in some cases. Complete bioabsorption, i.e.
complete weight loss, may take some time, although preferably complete
bioabsorption occurs within 12 months, most preferably within 6 months.
The absorbable polymer may be a naturally occurring polymer, such as a
bacterial polyester, or a synthetic polymer. Suitable synthetic absorbable
polymers include polymers selected from the group consisting of aliphatic
polyanhydrides (described in U.S. Pat. No. 4,757,128 incorporated by
reference herein), aromatic polyanhydrides (described in U.S. Pat. No.
5,264,540 incorporated by reference herein), radiation stable polylactones
(described in U.S. Pat. Nos. 4,435,590, 4,510,295, 4,532,928 and 4,689,424
incorporated by reference herein), poly(esteranhydrides) (as described in
patent application Ser. No. 03/062,865 filed May 14, 1993 and assigned to
Ethicon, Inc.), polyiminocarbonates, polyesters made by step growth
polymerization, especially polyesters that are absorbable like those made
from oxalic (described in U.S. Pat. No. 4,141,087 incorporated by
reference herein), malic, or tartaric acids, polyamides made by step
growth or ring opening polymerization, nontoxic structural
poly(aminoacids) or polypeptides made by the ring opening polymerization
of N-carboxyanhydrides or by genetic engineering, poly(hydroxybutyrate),
poly(hydroxybutyrate-co-hydroxyvalerate), other bacterially derived
polyesters (described in Lenz, etal. Macromolecules 22, 1106 (1989); 23
5059 (1990); 24 5256 (1991); 25 1852 (1992), polyphosphazenes,
polyesteramides like polymorpholinediones (described in U.S. Pat. Nos.
4,441,496 and 4,916,209 incorporated by reference herein), and block
copolymers of polyethylene glycol and polylactones (described in U.S. Pat.
No. 4,452,973 incorporated by reference herein). Preferably, the
absorbable polymer is a synthetic polymer. The preferred synthetic
absorbable polymers are derived from the class of monomers generally
referred to in the art as lactone monomers (including acid equivalents of
these monomers that may be used to form absorbable polymers). Examples of
lactone monomers include glycolide, lactide, 1,4-dioxanone, trimethylene
carbonate, .delta.-valerolactone, .epsilon.-caprolactone,
1,4-dioxepan-2-one, 1,5-dioxepan-2-one, and substituted equivalents of
these compounds as well as the cyclic dimers of these compounds.
Also envisioned within the scope of the invention are compositions composed
of copolymers of the above-mentioned lactone monomers. Random, block or
graft copolymers of any of the lactone monomers can be prepared to make
compositions which fall within the scope of this invention. In a similar
manner, polymeric blends can be used, in which absorbable polymers are
blended to prepare a mixture of the individual polymer components.
The preferred absorbable polymers are synthetic polymers derived from the
polymerization of lactide, glycolide and 1,4-dioxanone. The most preferred
polymers are the homopolymer of 1,4-dioxanone and copolymers of lactide
and glycolide. It is advantageous that the polymer have a molecular weight
which is sufficient for melt processing to prepare surgical or medical
devices.
The amount of poly[succinimide] filler which is sufficient to increase the
stiffness of the polymer will depend on numerous factors, including the
particular polymer chosen and the application for which the polymer
composition is used. The amount to increase the stiffness can be readily
determined empirically. However, as a general rule, the concentration of
the poly[succinimide] filler in the polymer can vary over a range from
about 10 to about 80 percent of the weight of the filled composition.
Preferably, from about 20 to about 40 weight percent of the
poly[succinimide] filler is used. If the concentration were less than
about 10 weight percent of filler, then the desired increase in stiffness
of the polymer may not be realized. Conversely, if the concentration of
filler were greater than about 80 weight percent, then the processability
of the composite may be compromised.
The filler may be in any structural form which is suitable for the
equipment being used to prepare the composition and which is necessary to
achieve the desired final properties. For example, the poly[succinimide]
filler may be a powder, or it could be in the form of continuous or staple
fibers. It may also be in the form of microfibers, whiskers, or plates.
Fibers may be the preferred form when uniaxial or biaxial orientation in
the polymer composition is desired. The greatest increases in mechanical
properties are achieved when the filler has a high aspect ratio. On the
other hand, a powder may be preferred when a uniform distribution of the
filler in the polymer matrix is desired. If processability is the primary
concern, then the filler is preferably in the form of a finely divided
powder. Such a finely divided powder is often easiest to uniformly
distribute throughout the polymer.
If a finely divided powder is used as the poly[succinimide] filler, then
the particle size distribution of the powder can vary over a wide range,
but it is typically preferred to have a particle size distribution ranging
from about 50 to about 150 microns. However, even particle sizes under
about 50 microns can be used to stiffen the absorbable polymer.
Poly[succinimides] are isolated and purified by precipitation.
Precipitation techniques may be used to control the size and to some
extent the shape of the poly[succinimide] filler. Generally, when a finely
divided powder is required, the precipitated poly[succinimide] is ground
and sifted through sieves to yield a relatively uniform particle size
distribution. A uniform distribution of these poly[succinimide] particles
in the polymer matrix is also desired to achieve the optimum properties.
The incorporation of the poly[succinimide] filler into the absorbable
polymer can be accomplished using conventional methods. Preferably, when a
finely divided powder is used as the filler, the poly[succinimide] powder
is dried, ground, and sifted through appropriate micron sieves until a
sufficient quantity of the particles of desired size distribution is
produced. The screened particles are desirably kept dry by storage under
vacuum until they can be dry blended with the absorbable polymer in an
appropriate mixer. The mixing operation should be performed until a
uniform dispersion of the poly[succinimide] particles in the polymer is
achieved. If the poly[succinimide] is used in the form of continuous or
staple fibers, then conventional techniques for the processing of fibrous
products can be used.
The poly[succinimide] filler may also be added to the monomer feed at the
time of the polymerization of the monomer or comonomers provided that
adequate mixing is used.
Once the compositions of this invention are made, they can be easily
processed using conventional melt processing techniques to prepare
numerous medical and surgical devices. The compositions can be extruded to
prepare fibers for sutures and ligatures. Preferably, the compositions are
injection molded to prepare a vast array of devices which are designed to
penetrate bodily tissue or to withstand heavy loads. Included among such
devices are surgical staples and ligating clips.
The following examples are intended to illustrate the preferred embodiments
of this invention. By no means should these examples be construed to limit
the scope and spirit of this invention as it is delineated in the appended
claims. Numerous additional embodiments will become readily apparent to
those skilled in this art.
EXAMPLES
EXAMPLE 1
PREPARATION OF POLY[SUCClNIMIDE] FROM D,L-ASPARTIC ACID
200.4 Grams (1.50 moles) of D,L-aspartic acid and 101.2 grams (0.878 moles)
of an 85 weight percent aqueous phosphoric acid solution were placed into
a three liter, three neck, round bottom flask equipped with a mechanical
stirrer, a nitrogen gas inlet with a Firestone valve, and a vent. This
suspension was heated with an oil bath to 200.degree. C. The mixture began
to boil, and the steam was carried out of the reaction flask by the stream
of nitrogen. After fifteen to thirty minutes, a vacuum hose with a pinch
clamp was connected to the vent, and a vacuum was slowly applied by
opening the pinch clamp in stages. The nitrogen gas was turned off during
the vacuum distillation. Foaming was a problem as the pressure in the
reaction chamber was reduced. Foaming was controlled by carefully
adjusting the pressure. Full vacuum was usually obtained after forty five
to sixty minutes. The reaction mixture was held under high vacuum at
200.degree. C. for two hours, and then, allowed to cool down to room
temperature under nitrogen.
1.5 Liters of dimethylformamide (DMF) were added to the reaction flask, and
the resulting mixture was heated to 150.degree. C. until all of the
poly[succinimide] had dissolved. The solution was transferred into a large
stainless steel blender and stirred vigorously while 3.75 liters of
distilled water were added. The tan powder was isolated by suction
filtration, washed with several liters of distilled water, and finally
washed with one liter of methanol. The filtercake was air dried on the
Buchner funnel and vacuum dried at 110.degree. C. for twenty four hours.
The vacuum trap was cleaned periodically during the devolatization cycle.
138 Grams of a light tan powder of poly[succinimide] were collected. The
inherent viscosity was 0.23 dL/g in DMF at 25.degree. C. (c=0.10 g/dL).
FTIR (KBr pellet, cm.sup.-1): 3490 (broad), 2954, 1801, 1714, 1389, 1363,
1288, 1257, 1214, 1162, 935, 700, 636. .sup.1 H NMR (300 MHz, d.sub.7
-DMF, ppm) .delta. 2.85 [bs, 1H], 3.35 [bs, 1H], 5.5 [broad two lines,
1H]. The glass transition temperature was 200.degree. C. as measured by
differential scanning calorimetry (DSC) at 20.degree. C. per minute under
nitrogen.
EXAMPLE 2
PREPARATION OF POLY[SUCCINIMIDE] FROM D-ASPARTIC ACID
50.0 Grams (0.376 moles) of D-aspartic acid and 25.3 grams (0.219 moles) of
an 85 weight percent aqueous phosphoric acid solution were placed into a
500 mL, three neck, round bottom flask equipped with a mechanical stirrer,
a distillation head, and a collection flask. The reaction flask was
immersed in an oil bath and connected to both a nitrogen gas line and a
vacuum line with a Firestone valve. The suspension was heated with an oil
bath to 200.degree. C. under an inert atmosphere. The mixture began to
boil, and water was collected. The collection flask was chilled with dry
ice. Some foaming occurred and the viscosity of the reaction mixture
increased. After about one hour, mechanical stirring was stopped and a
vacumm was slowly applied to the reaction mixture. Water continued to
distill out. Foaming was not a serious problem. The reaction mixture was
held at 200.degree. C. for two hours under high vacuum and then allowed to
cool down to room temperature under nitrogen.
275 Milliliters of DMF were added to the reaction flask, and the resulting
mixture was heated to 150.degree. C. until all of the poly[succinimide]
had dissolved. The solution was transferred into a 500 mL separatory
funnel and added into a large stainless steel blender containing two
liters of distilled water with vigorous stirring. A tan powder
precipitated out of solution and was isolated by suction filtration. The
filtercake was washed with several liters of distilled water and then with
about 500 mL of methanol, and air dried on the Buchner funnel. The wet
filtercake was a tan paste and weighed 169.3 grams, was transferred into a
dish, and finally vacuum dried at 110.degree. C. for twenty four hours.
The vacuum trap was cleaned periodically during this devolatization step.
35.6 grams of a tan material were isolated and ground into a fine power in
a mortar and pestle. The inherent viscosity of this poly[succinimide] was
0.39 dL/g in DMF at 25.degree. C. (c=0.10 g/dL). A broad endothermic
transition was observed by DSC between 200.degree. C. and 300.degree. C.
Thermal decomposition started to occur around 390.degree. C. as determined
by thermogravimetric analysis (TGA). The poly[succinimide] lost about 3.90
weight percent by the onset of decomposition.
EXAMPLE 3
PREPARATION OF POLY[SUCCINIMIDE] FROM L-ASPARTIC ACID
50.0 Grams (0.376 moles) of L-aspartic acid and 25.3 grams (0.219 moles) of
an 85 weight percent aqueous phosphoric acid solution were placed into a
500 mL, three neck, round bottom flask equipped with a mechanical stirrer,
a distillation head, and a collection flask. The reaction flask was
immersed in an oil bath and connected to both a nitrogen gas line and a
vacuum line with a Firestone valve. The suspension was heated with an oil
bath to 200.degree. C. under an inert atmosphere. The mixture began to
boil, and water was collected. The collection flask was chilled with dry
ice. Some foaming occurred and the viscosity of the reaction mixture
increased. After about one hour, mechanical stirring was stopped and a
vacumm was slowly applied to the reaction mixture. Water continued to
distill out. Foaming was not a serious problem this time. The reaction
mixture was held at 200.degree. C. for two hours under high vacuum and
then allowed to cool down to room temperature under nitrogen.
300 Milliliters of DMF were added to the reaction flask, and the resulting
mixture was heated to 150.degree. C. until all of the poly[succinimide]
had dissolved. The solution was transferred into a 500 mL separatory
funnel and added into a large stainless steel blender containing two
liters of distilled water with vigorous stirring. A tan powder
precipitated out of solution and was isolated by suction filtration. The
filtercake was washed with several liters of distilled water and then with
about 500 mL of methanol, and air dried on the Buchner funnel. 195 grams
of wet filtercake were vacuum dried at 110.degree. C. for twenty two
hours. The vacuum trap was cleaned periodically during the devolatization
process. 36.3 grams of a tan material were isolated and ground into a fine
power in a mortar and pestal. The inherent viscosity of this
poly[succinimide] was 0.38 dL/g in DMF at 25.degree. C. (c=0.10 g/dL). A
broad endothermic transition was observed by DSC between 200.degree. C.
and 300.degree. C. Thermal decomposition started to occur around
390.degree. C. as determined by TGA. The poly[succinimide] lost about 9.0
weight percent by the onset of decomposition.
EXAMPLE 4
IN VlVO ABSORPTION AND TISSUE REACTION STUDY
2.5 Grams of poly[succinimide], prepared as described in Example 1 and
having an inherent viscosity of 0.29 dL/g, were dissolved in 10 mL of DMF
at room temperature in a 50 mL Erlenmeyer flask. In the glove box, the
resulting viscous solution was poured into a silanized dish and covered
with a large beaker to slow down the evaporation of the solvent. After two
weeks, the film was still soft. The beaker was then replaced by the top
section of an uncapped one gallon milk jug with its bottom cut out to
speed the evaporation rate. After another two weeks, a brittle amber film
had formed. The film was then cut into 0.3.times.2.0 cm strips with a hot
spatula. The edges of the strips were sanded smooth with an emery board.
These poly[succinimide] strips were kept dry by storage in a vacuum oven
and were later placed in packages, sterilized by ethylene oxide exposure,
and sealed under nitrogen. No residual DMF was detected by 300 MHZ .sup.1
H NMR spectroscopy in the poly[succinimide] strips.
The sterilized strips of poly[succinimide] were evaluated for intramuscular
tissue reaction and absorption in rats. The tissue reaction at three and
seven days was slight to moderate. Nothing unusual was observed. The
tissue reaction decreased steadily with implantation time. After 56 days,
the poly[succinimide] was completely absorbed in some animals and almost
completely absorbed in others. A few small fragments of polymer remained.
The absorption of poly[succinimide] was checked again after 119 days, at
which time it was observed that all of the poly[succinimide] had
completely disappeared.
EXAMPLE 5
GRINDING AND SIFTING OF POLYSUCCINIMIDES
The batches of poly[succinimide] from Examples 2 and 3 were ground into
fine powders using a mortar and pestle. Each material was sifted through a
150 micron sieve and then through a 50 micron sieve to produce 10 grams of
material consisting of particle sizes ranging from 150 to 50 microns
(i.e., material sifted through 150 .mu.m sieve but not through 50 .mu.m
sieve). The ground and screened materials were stored in a vacuum oven at
room temperature.
The poly[succinimide] of Example 2 was also ground using a mortar and
pestle to yield 8.0 grams of material passing through a 50 micron sieve.
EXAMPLE 6
INJECTION MOLDING OF POLY[1,4-DIOXANONE] BARBELLS
Cylindrical barbells were molded from poly[1,4-dioxanone] having an
inherent viscosity of 1.8 dL/g in hexafluoroisopropanol at 30.degree. C.
(c=0.10 g/dL) on a benchtop injection molding machine (manufactured by
Custom Scientific Instruments, Mini Max Molder Model CS-182MMX). These
barbells were molded between 120.degree. C. and 130.degree. C.; the
residence time in the Mini Max Molder was approximately three minutes; and
the barbells did not adhere to the mold. The barbells were annealed at
85.degree. C. for 18 hours under a nitrogen atmosphere.
EXAMPLE 7
INJECTION MOLDING OF POLY[1,4-DIOXANONE] BARBELLS AFTER BEING KNEADED IN A
BRABENDER PLASTI-CORDER
The same batch of poly[1,4-dioxanone] used in Example 6 (I.V.=1.8 dL/g) was
placed in the small mixing bowl of a Brabender Plasti-Corder (Model PL
2000) equipped with roller blades and heated at 130.degree. C. for thirty
minutes with the blades turning at five revolutions per minute. Then, the
mixing bowl was disassembled, and the polymer removed. The
poly[1,4-dioxanone] was stored in the dark under vacuum prior to grinding.
The polymer was frozen in liquid nitrogen and ground in a Wiley mill to
pass through a 6mm screen. The resulting course ground resin of
poly[1,4-dioxanone] was stored under vacuum for at least 24 hours prior to
injection molding. Cylindrical barbells of this kneaded
poly[1,4-dioxanone] were molded and annealed as described in Example 6.
EXAMPLE 8
INJECTION MOLDING OF POLY[1,4-DIOXANONE] BARBELLS AFTER BEING KNEADED IN
THE BRABENDER EXTRUDER
Example 7 was repeated. This example is just another control experiment
performed at the time the smaller particle size blend was prepared and
molded.
EXAMPLE 9
INJECTION MOLDING OF POLY[SUCCINIMIDE] FILLED POLY[1,4-DIOXANONE] BARBELLS
9.0 Grams of the 150-50 micron particle size poly[succinimide], made in
Example 2 and sifted in Example 5, were combined with 21.0 grams of
poly[1,4-dioxanone] having an inherent viscosity of 1.8 dL/g in a jar and
shaken by hand for a few minutes. The mixture was then added to the small
mixing bowl of a Brabender PlastiCorder at 130.degree. C. and blended for
thirty minutes with the blades turning at five revolutions per minute. The
mixing bowl was disassembled, and the blend was removed. The
poly[succinimide] filled poly[1,4-dioxanone] blend was stored in the dark
under vacuum. The blend was frozen in liquid nitrogen and ground in a
Wiley mill to pass through a 6 mm screen. After grinding, the samples were
stored under vacuum for at least 24 hours prior to injection molding.
Cylindrical barbells of this poly[succinimide] filled poly[1,4-dioxanone]
blend were molded on a Mini Max benchtop injection molding machine between
150.degree. C. and 170.degree. C. in order to fill the mold completely,
whereas the unfilled poly[1,4-dioxanone] was molded between 120.degree. C.
and 130.degree. C. The residence time in the Mini Max was approximately
three minutes, and the barbells did not adhere to the mold. The resulting
barbells were placed in a glass dish and were annealed at 85.degree. C.
for 18 hours under a nitrogen atmosphere.
EXAMPLE 10
INJECTION MOLDING OF POLY[SUCCINIMIDE] FILLED POLY[1,4-DIOXANONE] BARBELLS
9.0 Grams of the 150-50 micron particle size poly[succinimide], made in
Example 3 and sifted in Example 5, were combined with 21.0 grams of
poly[1,4-dioxanone] having an inherent viscosity of 1.8 dL/g in a jar and
shaken by hand for a few minutes. The mixture was then added to the small
mixing bowl of a Brabender PlastiCorder at 130.degree. C. and blended for
thirty minutes with the blades turning at five revolutions per minute. The
mixing bowl was disassembled, and the blend was removed. The
poly[succinimide] filled poly[1,4-dioxanone] blend was stored in the dark
under vacuum. The blend was frozen in liquid nitrogen and ground in a
Wiley mill to pass through a 6 mm screen. After grinding, the samples were
stored under vacuum for at least 24 hours prior to injection molding.
Cylindrical barbells of this poly[succinimide] filled poly[1,4-dioxanone]
blend were molded on a Mini Max benchtop injection molding machine between
150.degree. C. and 170.degree. C. The residence time in the Mini Max was
approximately three minutes, and the barbells did not adhere to the mold.
The resulting barbells were placed on a glass dish were annealed at
85.degree. C. for 18 hours under a nitrogen atmosphere.
EXAMPLE 11
INJECTION MOLDING OF POLY[SUCCINIMIDE] FILLED POLY[1,4-DIOXANONE] BARBELLS
8.0 Grams of the 50 micron or less particle size poly[succinimide], made in
Example 2 and sifted in Example 5, were added to 18.6 grams of
poly[1,4-dioxanone] having an inherent viscosity of 1.8 dL/g in a jar and
shaken by hand for a few minutes. The mixture was then added to the small
mixing bowl of a Brabender Plasti-Corder at 130.degree. C. and blended for
thirty minutes with the blades turning at five revolutions per minute. The
mixing bowl was disassembled, and the blend was removed. The
poly[succinimide] filled poly[1,4-dioxanone] blend was stored in the dark
under vacuum. The blend was frozen in liquid nitrogen and ground in a
Wiley mill to pass through a 6 mm screen. After grinding, the samples were
stored under vacuum for at least 24 hours prior to injection molding.
Cylindrical barbells of this polysuccinimide filled poly[1,4-dioxanone]
blend were molded on a Mini Max benchtop injection molding machine between
150.degree. C. and 170.degree. C. The residence time in the Mini Max was
approximately three minutes, and the barbells were placed in a glass dish
did not adhere to the mold. The resulting barbells were placed in a glass
dish and were annealed at 85.degree. C. for 18 hours under a nitrogen
atmosphere.
EXAMPLE 12
TENSILE TESTING OF THE BARBELLS
The tensile properties of the cylindrical barbells of poly[1,4-dioxanone]
and of the poly[succinimide] filled poly[1,4-dioxanone] blends are shown
in Tables I and II for the two different particle size fillers.
TABLE I
__________________________________________________________________________
Poly[succinimide] Filled Poly[1,4-dioxanone]
(150-50 Micron Particle Size)
Tensile Properties
Yield Yield
Breaking
Strain
Young's
Percent
Example
Strength
Strain
Strength
at Modulus
Modulus
Number
(psi) (%) (psi) Break (%)
(ksi)
Increase
__________________________________________________________________________
Ex. 6
6700 23 6130 34 54 NA
Control
S.D. 370 2 390 5 6
Ex. 7
7080 21 4520 57 48 NA
Kneaded
Control
S.D. 300 4 800 44 5
Ex. 9
8270 14 7220 25 77 60
30 wt. %
Filler
S.D. 370 1 590 4 6
Ex. 10
7700 13 7250 16 76 58
30 wt. %
Filler
S.D. 160 1 310 1 9
__________________________________________________________________________
S.D. means standard deviation.
TABLE II
__________________________________________________________________________
Poly[succinimide] Filled Poly[p-dioxanone]
(50 Microns and less Particle Size)
Tensile Properties
Yield Yield
Breaking
Strain
Young's
Percent
Example
Strength
Strain
Strength
at Modulus
Modulus
Number
(psi) (%) (psi) Break (%)
(ksi)
Increase
__________________________________________________________________________
Ex. 6
6700 23 6130 34 54 NA
Ex. 8
7320 19 5140 74 50 NA
Kneaded
Control
S.D. 430 2 1000 53 10
Ex. 11
7320 15 6540 25 69 38
30 wt. %
Filler
S.D. 290 1 415 4 5
__________________________________________________________________________
S.D. means standard deviation.
Two poly[1,4-dioxanone] controls were employed. The first control (Example
6) was simply the poly[1,4-dioxanone] used in all of the experiments,
having an inherent viscosity of 1.8 dL/g. This material was injection
molded at 120.degree. C. into barbells which were then annealed and
tensile tested. The second poly[1,4-dioxanone] controls (Examples 7 and 8)
were injection molded after being melted and kneaded in the Brabender
Plastic-Corder in the same way that the poly[succinimide] filled
poly[1,4-dioxanone] blends were prepared. As shown in the first two rows
of Table I, barbells of the unkneaded and kneaded poly[1,4-dioxanone] had
virtually the same mechanical properties, indicating that the melt
blending process used in this study did not alter the poly[1,4-dioxanone]
to any appreciable extent.
Two poly[succinimide] filled poly[1,4-dioxanone] blends (Examples 9 and 10)
were prepared using two different batches of poly[succinimide] (Examples 2
and 3) of similar molecular weight having a particle size between 150 and
50 microns. These blends contained 30 weight percent poly[succinimide].
The tensile properties of these filled systems are shown in the last two
rows of Table I and are almost identical. The Young's modulus of the
poly[succinimide] filled poly[1,4-dioxanone] increased about 60 percent
over that of the unfilled poly[1,4-dioxanone] , and the elongation to
break decreased. Furthermore, the tensile strength of the
poly[succinimide] filled poly[1,4-dioxanone] was slightly higher than that
of the unfilled poly[1,4-dioxanone] which suggests that the
poly[succinimide] filler is evenly dispersed and has reasonably good
adhesion to the poly[1,4-dioxanone] matrix.
Similarly, as listed in Table II, barbells made from the blend of
poly[1,4-dioxanone] and poly[succinimide] consisting of particles of 50
microns or less (Example 11) showed a 38 percent increase in the Young's
modulus over that of virgin poly[1,4-dioxanone] barbells (Example 8).
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